P358: HYPER-CVAD WITH BLINATUMOMAB AND INOTUZUMAB OZOGAMICIN FOR PATIENTS WITH NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME-NEGATIVE B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA: A PHASE II STUDY
Authors: Nicholas Short, Elias Jabbour, Nitin Jain, Fadi Haddad, Musa Yilmaz, Lewis Nasr, Alessandra Ferrajoli, Tapan Kadia, Yesid Alvarado, Abhishek Maiti, Walid Macaron, Marianne Zoghbi, Cedric Nasnas, Rebecca Garris, Min Zhao, Marina Konopleva, Farhad Ravandi, Hagop Kantarjian
Journal: HemaSphere (2023)

Background: Blinatumomab consolidation improves overall survival (OS) in adults with newly diagnosed B-cell ALL, regardless of measurable residual disease (MRD) status. We hypothesized that early incorporation of inotuzumab ozogamicin (INO) in patients (pts) with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL receiving frontline intensive chemotherapy plus blinatumomab would further deepen responses and improve outcome. Aims: We evaluated the efficacy and safety of hyper-CVAD with sequential blinatumomab, with or without INO, in pts with newly diagnosed Ph-negative B-cell ALL. Methods: Pts 14-59 years of age with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (with the exception of CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of blinatumomab consolidation (4 total cycles with INO). Results: To date, 69 pts have been treated (38 without INO and 31 with INO). Baseline characteristics are summarized in Table 1. The median age was 34 years (range, 18-59). Among 53 pts with active disease at study entry, 100% achieved CR. MRD negativity by flow cytometry was achieved in 56/59 evaluable pts (95%). Two of the 3 pts who did not achieve MRD negativity were later found to have a NUP214::ABL1 fusion, and 1 had KMT2A rearrangement. The median follow-up of the entire cohort is 26 months (range, 4 to 73 months). Overall, 8 pts (12%) relapsed while on study, 22 (32%) underwent stem cell transplant (SCT) in first remission (2 of whom relapsed post-SCT), 2 (3%) died in CR, and 37 (54%) remain in continuous remission without SCT. For the entire cohort, the estimated 3-year OS was 87% and the 3-year continuous remission duration was 83%. With a median follow-up in the INO cohort of 15 months, 3 pts (10%) have relapsed, all with CNS-only relapses, and none has died. The 15-month OS in the cohorts with and without INO were 100% and 87%, respectively (P=0.06) (Figure 1). One patient discontinued blinatumomab due to recurrent grade 2 neurotoxicity. No pts have discontinued INO due to toxicity and no cases of SOS/VOD have been observed. Summary/Conclusion: In pts with newly diagnosed Ph-negative B-cell ALL receiving hyper-CVAD with sequential blinatumomab, the addition of INO is safe and may improve survival.Keywords: Acute lymphoblastic leukemia, Clinical trial, Phase II